Humanized mice refer to mice stably reconstituted or engrafted with human tissues/cells, such as human immune and liver cells. Humanized mice with a reconstituted human immune system are constructed by engrafting immunodeficient mice with human hematopoietic stem cells (HSCs), which then give rise to all human blood lineage cells throughout the lifetime of the mice.
We have made significant contributions to the development of the humanized mouse technology by i) expanding HSCs in vitro for large scale construction of humanized mice (Drake et al 2011; Khoury et al 2011), ii) expressing human cytokines in recipient mice to enhance the reconstitution and function of human immune cells (Chen et al 2009), including myeloid lineage cells (Chen et al 2012; Li et al 2013), and iii) generating humanized mice with human liver cells and matching human immune system (Chen et al 2013).
The stable reconstitution of human cells in mice provides a unique opportunity to model diseases mediated by human cells in the presence of autologous human immune system. By expressing proto-oncogenes Bcl-2 and Myc in human B-lineage cells, we have constructed double-hit lymphoma in humanized mice that exhibits characteristic histopathological features of the human tumor, including infiltration into the central nervous system (Leskov et al, 2012). We have evaluated the efficacy of anti-CD52 antibody (alentuzumab) for treating double-hit lymphoma and identified a potent synergy between alentuzumab and cyclophosphamide in eliminating bone marrow residual tumor cells (Pallasch et al, 2014). We have also developed humanized mouse models of infectious diseases for various pathogens that infect only human cells, including dengue virus (Sridharan et al 2013), Plasmodium falciparum (Chen et al 2014), and Epstein Barr Virus (EBV) (Oo et al submitted).
Moving forward, we are interested in studying human diseases and interventions in humanized mice, including:
- Molecular mechanisms underlying the progression of human hematologic cancers,
- Mechanisms of cancer immunotherapies in mice with human cancer and autologous human immune system,
- Molecular and cellular mechanisms of immune responses to dengue virus and malaria parasite,
- Vaccine development for dengue and malaria.
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